Abstract
The purpose of this study is to report the changes of CYP2E1, CYP1A2, CYP2B1/2, CYP2C11, CYP3A23, and CYP3A2 expression and pharmacokinetics and tissue distribution of chlorzoxazone (CZX) and 6-hydroxychlorzoxazone (OH-CZX) in rats with acute renal failure induced by uranyl nitrate (U-ARF), and the role of CYP3A23 and CYP3A2 in the formation of OH-CZX in rats with U-ARF. In rats with U-ARF, CYP2C11 decreased to 20% of control, whereas CYP2E1 and CYP3A23 increased 2.3 and 4 times, respectively, compared with control. But expression of CYP1A2 and CYP2B1/2 was not changed by U-ARF. After i.v. administration of CZX at a dose of 20 mg/kg to rats with U-ARF, the areas under the plasma concentration-time curve from time 0 to time infinity (AUCs) of CZX and OH-CZX were significantly smaller and greater, respectively, than those in control rats. In rats with U-ARF, CZX was below the detection limit at 120 min in all rat tissues studied, whereas it was detected in all tissues of control rats at both 30 and 120 min. However, in control rats, OH-CZX was below the detection limit at both 30 and 120 min in all rat tissues except kidney, whereas it was detected in all tissues of rats with U-ARF at both 30 and 120 min. Based on results from supporting experiments with DDT and 2,2-bis(4-chlorophenyl)1,1-dichloroethylene treatment of rats, the contribution of CYP3A23 and CYP3A2 to the enhanced formation of OH-CZX in rats with U-ARF is likely to be negligible.
Footnotes
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↵ 1 Abbreviations used are: CZX, chlorzoxazone; OH-CZX, 6-hydroxychlorzoxazone; U-ARF, acute renal failure induced by uranyl nitrate; AUC, area under the plasma concentration-time curve from time zero to time infinity; CL, time-averaged total body clearance; CLR, time-averaged renal clearance; CLNR, time-averaged nonrenal clearance; DDE, 2,2-bis(4-chlorophenyl)1,1-dichloroethylene; HPLC, high-performance liquid chromatography; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; CLint, intrinsic OH-CZX formation clearance; MRT, mean residence time; Vss, apparent volume of distribution at steady state; CLCR, creatinine clearance; ARF, acute renal failure; GI0–8 h, percentage of i.v. dose of CZX recovered from gastrointestinal tract at 8 h; T/P, tissue-to-plasma ratio; P450, cytochrome P450; DA-1131, (IR,5S,6S)-(2S,4S)-2-[(E)-3-methansulfonyl amino-1-propenyl]pyrrolidine-4-ylthiol-6-[(R)-1-hydroxy-ethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid; DA-125, (8S,10S)-8-(3-aminopropanoyloxyacetyl)-10-[(2,6-dideoxy-2-fluro-α-l-talopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8,11-trihydroxy-methoxy-5,12-naphthacenedione; YJA-20379-8, 3-butyryl-4-[5-R-(+)-methylbenzylamino]-8-ethoxy-1,7-naphthyridine.
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This work was supported in part by Korea Research Foundation (2001-042-F00115).
- Received May 30, 2002.
- Accepted March 12, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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